All ETDs from UAB

Advisory Committee Chair

Sarah M Clinton

Advisory Committee Members

Yogesh Dwivedi

Ilan A Kerman

Farah D Lubin

David G Standaert

J David Sweatt

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Anxiety disorders are the most commonly diagnosed mental illness in the United States. Yet current treatment options are of limited efficacy, resulting in chronic disability for many patients. A greater mechanistic understanding of the neural states that cause anxiety behavior is necessary to develop better treatments for anxiety disorders. Since rodent models provide greater opportunity for investigating cellular and molecular under-pinnings of anxiety-like behavior, the present studies utilized rats bred for High Response to novelty (High Responders, HRs) and Low Response to novelty (Low Responders, LRs) which naturally exhibit low and high levels of anxiety respectively. Because the HR/LR anxiety phenotypes are heritable they provide a unique opportunity to probe the genetic architecture of anxiety-like behavior. The present study began by determining which brain regions might contribute to the HR/LR anxiety-phenotype. HRs display greater activation of serotonergic cells in the dorsal raphe and less activation across the amygdala following defensive burying stress compared to LRs. Next-generation sequencing of mRNA and microRNAs (miRNA) from these regions identified numerous differences across the transcriptome of HRs and LRs. Of particular interest was miR-101a-3p which is highly expressed and up-regulated in the amygdala of LR rats. miR-101a-3p represses expression of the histone methyltransferase enhancer of zeste homolog 2 (Ezh2), a critical component of the polycomb repressive complex 2, which is necessary for trimethylation of histone 3 lysine 27 (H3K27me3) and gene silencing. Reduced expression of miR-101a-3p in the amygdala of HR rats was as-sociated with increased expression of its target protein Ezh2 and total H3K27me3. Con-sistent with the hypothesis that amygdala expression of miR-101a-3p contributes to anxi-ety-like behavior, viral overexpression of miR-101a-3p in the amygdala of HRs increased anxiety-like behavior in both the open field and elevated plus maze. Further, small inter-fering RNA knockdown of the miR-101a-3p target Ezh2 also increased anxiety-like be-havior in HRs, albeit to a lesser extent than miR-101a-3p overexpression. Together these findings indicate that the HR/LR rodent lines provide a useful tool for investigating ge-netic and molecular mechanisms of anxiety behavior and specifically that miR-101a-3p regulation of Ezh2 in the amygdala contributes to anxiety behavior.

Share

COinS